Influenza epidemics exact a formidable toll on world health. Last year, the emergence of a novel influenza A H1N1 viral strain created a pandemic, producing illness around the globe. Additionally, the related avian influenza A viral strain, H5N1, represents a potentially catastrophic global health risk. Like all viruses, influenza A virus exploits host factors to replicate. To defend against this exploitation, the host mobilizes factors to confront the virus. A distinct class of protein signaling molecules, the interferons (IFNs), orchestrates a large component of this anti-viral response at both a cellular and organismal level. IFN stimulation results in over 2000 gene products being differentially regulated after IFN stimulation. To find host-cell modifiers of influenza A H1N1 viral infection, we completed a large scale genetic screen and detected several proteins which are important in decreasing influenza A virus infection, including a role for interferon-inducible trans-membrane protein 3 (IFITM3). The loss of IFITM3 resulted in elevated viral replication in multiple cell lines tested, and proved to be critical for IFN-induced viral resistance, accounting for 50% to 80% of IFN's protective ability. IFITM3 belongs to a family of four closely related proteins in humans, and five proteins in mice. This application aims to elucidate the role of the IFITM proteins in the host response to influenza A virus infection. Successful achievement of the aims of this proposal will provide in depth knowledge of the actions of the IFITM proteins and will inform us more fully on the innate interferon response to viruses. Relevance to Public Health: Influenza A virus is a threat to world health. Our previous studies have shown that the IFITM proteins play an important role in blocking influenza A virus infection. We are studying how IFITM3 decreases influenza A virus infection, and trying to find ways to use this knowledge to inhibit viral infections.